Arf induces p53-dependent and -independent antiproliferative genes

Mei Ling Kuo, Eric J. Duncavage, Rose Mathew, Willem Den Besten, Deqing Pei, Deanna Naeve, Tadashi Yamamoto, Cheng Cheng, Charles J. Sherr, Martine F. Roussel

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

The tumor suppressor p19Arf (p14ARF in humans), encoded by the Ink4a/Arf locus, is mutated, deleted, or silenced in many forms of cancer. p19Arf induces growth arrest by antagonizing the activity of the p53-negative regulator, Mdm2, thereby inducing a p53 transcriptional response, p19Arf can also inhibit cell cycle progression of mouse embryo fibroblasts lacking Cip1 or lacking both Mdm2 and p53, although in the absence of p53, arrest occurs more slowly. Profiling with high-density oligonucleotide GeneChips and cDNA microarrays was used to interrogate mouse genes, the expression of which was induced or suppressed by a conditionally regulated Arf gene. Cluster analysis of temporal gene expression patterns and validation of the results by RNA analysis identified Arf-responsive genes whose induction was both p53-dependent and -independent. The latter included four members of the B-cell translocation gene family (Btg1, Btg2, Btg3, and Tob1) that were demonstrated to inhibit cell proliferation in primary mouse embryo fibroblasts expressing or lacking functional p53. Together, the results indicate that p19Arf induces a broad spectrum of proteins that likely act in concert to arrest cell proliferation.

Original languageEnglish
Pages (from-to)1046-1053
Number of pages8
JournalCancer research
Volume63
Issue number5
StatePublished - Mar 1 2003

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